Pharmacokinetics, disposition and metabolism of 546C88 (L-NG-methylarginine hydrochloride) in rat and dog.
1. 14C-546C88 (14C-L-NG-methylarginine hydrochloride) was administered to rat and dog as a single 5-min intravenous infusion at 1.7 mg/kg (20 mg/kg/h) to aid in the preclinical safety evaluation of the compound. 2. The distribution and elimination of parent compound from plasma was rapid in both species. 3. Drug-derived radioactivity was eliminated slowly. There was up to 39% of the dose retained in the carcasses at the end of the 7-day collection periods. The main route of elimination was as 14CO2 in the expired air. Less than 8% of the dose was excreted in the urine, and < 5% in the faeces. 4. Drug derived radioactivity was widely distributed throughout the body with highest concentrations in tissues with a high protein turnover, such as glandular tissue and liver. 5. 14C-546C88 appeared to be eliminated primarily by metabolism and subsequent putative amino acid catabolism, resulting in retention of drug-derived radioactivity in tissues, and ultimate elimination as 14CO2 in the expired air. Potential routes of metabolism of 546C88 have been identified.
Schwartz
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S
Department of International Development Support, Bioanalysis and Drug Metabolism, Glaxo Wellcome Ltd, Ware, UK.
Clare
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R
Devereux
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Sheung
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CF
D000818:Animals; D001345:Autoradiography; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D007262:Infusions, Intravenous; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D014018:Tissue Distribution
D004791:Enzyme Inhibitors; D019335:Nitroarginine; D019001:Nitric Oxide Synthase